US7718652B2ActiveUtilityPatentIndex 41
Substituted benzothiadiazinedioxide derivatives and methods of their use
Est. expiryDec 12, 2026(~0.4 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 9/00A61P 25/00A61P 1/00C07D 285/16A61P 15/00
41
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References
68
Claims
Abstract
The present invention is directed to substituted benzothiadiazinedioxide derivatives of formula I: or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions, including, inter alia, vasomotor symptoms, sexual dysfunction, gastrointestinal disorders and genitourinary disorder, depression disorders, endogenous behavioral disorders, cognitive disorders, diabetic neuropathy, pain, and other diseases or disorders.
Claims
exact text as granted — not AI-modified1. A compound of formula I:
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;
wherein:
n is an integer from 1 to 3
m is an integer from 0 to 4;
X 1 is R 1 and X 2 is W; or
X 1 is W and X 2 is R 1 ;
W is:
R 1 is C 6 -C 10 aryl substituted with 0-3 R 11 or heteroaryl substituted with 0-3 R 11 ;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol, or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ;
R 3 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ; or
R 2 and R 3 , together with the nitrogen through which they are attached, form a heterocyclic ring or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , where any carbon ring atom may be optionally substituted with R 12 , and where said additional N atom may be optionally substituted with C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl substituted with 0-3 R 14 , heteroaryl substituted with 0-3 R 14 , alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 5 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 15 , C 6 -C 10 aryl-C 1 -C 6 alkyl where said aryl portion is substituted with 0-3 R 15 , heteroaryl substituted with 0-3 R 15 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 15 ;
R 6 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 16 , C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 16 , heteroaryl substituted with 0-3 R 16 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 16 ;
R 7 is, independently at each occurrence, H, alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
R 7 and one of said R 2 and R 3 , together with the nitrogen and carbon through which they are attached, may optionally form a heterocyclic or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally substituted with R 13 and any additional N atom substituted with C 1 -C 4 alkyl;
R 11 and R 12 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 13 , R 14 , R 15 , and R 16 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
wherein 1-3 carbon atoms in ring A may optionally be replaced with N.
2. The compound of claim 1 , wherein:
n is an integer from 1 to 2.
3. The compound of claim 1 , wherein:
m is an integer from 0 to 1.
4. The compound of claim 1 , wherein:
R 1 is C 6 -C 10 aryl substituted with 0-3 R 11 .
5. The compound of claim 1 , wherein:
R 1 is phenyl, tolyl, xylyl, methoxy-phenyl, fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl, fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl trifluoromethoxy-phenyl, methyl-fluoro-phenyl, methoxy-fluoro-phenyl, or naphthyl.
6. The compound of claim 1 , wherein:
R 1 is heteroaryl substituted with 0-3 R 1 .
7. The compound of claim 1 , wherein:
R 1 is pyridinyl, methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.
8. The compound of claim 1 , wherein:
R 2 is H, methyl, ethyl, cyclopropyl, or n-butyl.
9. The compound of claim 1 , wherein:
R 2 is hydrogen or methyl.
10. The compound of claim 1 , wherein:
R 3 is H, methyl, ethyl, cyclopropyl, or n-butyl.
11. The compound of claim 1 , wherein:
R 3 is hydrogen or methyl.
12. The compound of claim 1 , wherein:
R 2 and R 3 , together with the nitrogen through which they are attached, form a heterocyclic ring of 6 ring atoms, where one carbon may be optionally replaced with O.
13. The compound of claim 1 , wherein:
R 4 is, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , nitrile, or C 6 -C 10 aryl substituted with 0-3 R 1 .
14. The compound of claim 1 , wherein:
R 4 is, independently at each occurrence, methyl, methoxy, fluoro, chloro, bromo, CF 3 , OCF 3 , nitrile, or phenyl.
15. The compound of claim 1 , wherein:
R 5 is H, C 1 -C 6 alkyl, or phenyl.
16. The compound of claim 1 , wherein:
R 5 is H or methyl.
17. The compound of claim 1 , wherein:
R 6 is H, C 1 -C 6 alkyl, or phenyl.
18. The compound of claim 1 , wherein:
R 6 is H or methyl.
19. The compound of claim 1 , wherein X 1 is W and X 2 is R 1 .
20. The compound of claim 1 , wherein X 1 is R 1 and X 2 is W.
21. The compound of claim 1 , selected from the group consisting of:
3-(2,2-dioxido-1-phenyl-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl)-N-methylpropan-1-amine;
3-[1-(3-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
N-methyl-3-[1-(3-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propan-1-amine;
3-[1-(3-methoxyphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
3-[1-(4-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
3-[1-(3-chloro-4-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
3-[1-(4-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
N-methyl-3-[1-(4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propan-1-amine;
3-[1-(4-methoxyphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
3-[1-(3,4-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
3-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
N-{3-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propyl}cyclopropanamine;
4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
N-{4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]butyl}cyclopropanamine;
3-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
N-{3-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propyl}cyclopropanamine;
4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
N-{4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]butyl}cyclopropanamine;
(2S)-4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-1-(methylamino)butan-2-ol;
(2S)-4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-1-(methylamino)butan-2-ol;
3-[3-(2-fluorophenyl)-2,2-dioxido-3,4-dihydro-1H-2,1,3-benzothiadiazin-1-yl]-N-methylpropan-1-amine;
4-[1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-fluoro-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-fluoro-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-fluoro-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-fluoro-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-fluoro-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-chloro-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-chloro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-chloro-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-chloro-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-chloro-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-chloro-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-methyl-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-methyl-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-methyl-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-methyl-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-methyl-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-methyl-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-cyano-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-cyano-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-cyano-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-cyano-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-cyano-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[6-cyano-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine;
4-[1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-fluoro-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-fluoro-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-fluoro-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-fluoro-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-fluoro-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-chloro-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-chloro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-chloro-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-chloro-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-chloro-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-chloro-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-methyl-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-methyl-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-methyl-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-methyl-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-methyl-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-methyl-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-cyano-1-phenyl-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-cyano-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-cyano-1-(2,6-difluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-cyano-1-(2-fluoro-4-methylphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-cyano-1-(2-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine;
4-[6-cyano-1-(2,4,6-trifluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine; and
pharmaceutically acceptable salts thereof.
22. The compound of claim 1 , wherein said pharmaceutically acceptable salt is a hydrochloride.
23. A composition, comprising:
a. at least one compound of formula I:
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;
wherein:
n is an integer from 1 to 3
m is an integer from 0 to 4;
X 1 is R 1 and X 2 is W; or
X 1 is W and X 2 is R 1 ;
W is:
R 1 is C 6 -C 10 aryl substituted with 0-3 R 11 or heteroaryl substituted with 0-3 R 11 ;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol, or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ;
R 3 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ; or
R 2 and R 3 , together with the nitrogen through which they are attached, form a heterocyclic ring or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , where any carbon ring atom may be optionally substituted with R 12 , and where said additional N atom may be optionally substituted with C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl substituted with 0-3 R 14 , heteroaryl substituted with 0-3 R 14 , alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 5 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 5 , C 6 -C 10 aryl-C 1 -C 6 alkyl where said aryl portion is substituted with 0-3 R 15 , heteroaryl substituted with 0-3 R 15 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 15 ;
R 6 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 16 , C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 16 , heteroaryl substituted with 0-3 R 16 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 16 ;
R 7 is, independently at each occurrence, H, alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
R 7 and one of said R 2 and R 3 , together with the nitrogen and carbon through which they are attached, may optionally form a heterocyclic or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally substituted with R 13 and any additional N atom substituted with C 1 -C 4 alkyl;
R 11 and R 12 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 13 , R 14 , R 15 , and R 16 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
wherein 1-3 carbon atoms in ring A may optionally be replaced with N; and
b. at least one pharmaceutically acceptable carrier.
24. A method for treating a condition selected from the group consisting of a vasomotor symptom, sexual dysfunction, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, endogenous behavioral disorder, diabetic neuropathy, and pain in a subject in need thereof comprising the step of:
administering to said subject an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;
wherein:
n is an integer from 1 to 3
m is an integer from 0 to 4;
X 1 is R 1 and X 2 is W; or
X 1 is W and X 2 is R 1 ;
W is:
R 1 is C 6 -C 10 aryl substituted with 0-3 R 11 or heteroaryl substituted with 0-3 R 11 ;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol, or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ;
R 3 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ; or
R 2 and R 3 , together with the nitrogen through which they are attached, form a heterocyclic ring or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , where any carbon ring atom may be optionally substituted with R 12 , and where said additional N atom may be optionally substituted with C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl substituted with 0-3 R 14 , heteroaryl substituted with 0-3 R 14 , alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 5 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 15 , C 6 -C 10 aryl-C 1 -C 6 alkyl where said aryl portion is substituted with 0-3 R 15 , heteroaryl substituted with 0-3 R 15 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 15 ;
R 6 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 16 , C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 16 , heteroaryl substituted with 0-3 R 16 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 16 ;
R 7 is, independently at each occurrence, H, alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
R 7 and one of said R 2 and R 3 , together with the nitrogen and carbon through which they are attached, may optionally form a heterocyclic or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally substituted with R 13 and any additional N atom substituted with C 1 -C 4 alkyl;
R 11 and R 12 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 13 , R 14 , R 15 , and R 16 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
wherein 1-3 carbon atoms in ring A may optionally be replaced with N;
or pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
25. The method of claim 24 , wherein said vasomotor symptom is hot flush.
26. The method of claim 24 , wherein said sexual dysfunction is desire-related or arousal-related.
27. The method of claim 24 , wherein said condition is chronic fatigue syndrome.
28. The method of claim 24 , wherein said condition is fibromyalgia syndrome.
29. The method of claim 24 , wherein said condition is a depression disorder selected from the group consisting of major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, social phobia, and combinations thereof.
30. The method of claim 24 , wherein said condition is diabetic neuropathy.
31. The method of claim 24 , wherein said condition is pain.
32. The method of claim 31 , wherein said pain is acute centralized pain, acute peripheral pain, or a combination thereof.
33. The method of claim 31 , wherein said pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.
34. The method of claim 31 , wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.
35. The method of claim 34 , wherein said neuropathic pain is associated with diabetes, post traumatic pain of amputation, lower back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection, metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions, or a combination thereof.
36. The method of claim 35 , wherein said neuropathic pain is post-herpetic neuralgia.
37. The method of claim 34 , wherein said visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, or a combination thereof.
38. The method of claim 31 , wherein said pain is female-specific pain.
39. A process for the preparation of a compound of Formula II:
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;
wherein:
n is an integer from 1 to 3
m is an integer from 0 to 4;
R 1 is C 6 -C 10 aryl substituted with 0-3 R 11 or heteroaryl substituted with 0-3 R 11 ;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol, or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ;
R 3 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ; or
R 2 and R 3 , together with the nitrogen through which they are attached, form a heterocyclic ring or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , where any carbon ring atom may be optionally substituted with R 12 , and where said additional N atom may be optionally substituted with C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl substituted with 0-3 R 14 , heteroaryl substituted with 0-3 R 14 , alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 5 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 15 , C 6 -C 10 aryl-C 1 -C 6 alkyl where said aryl portion is substituted with 0-3 R 15 , heteroaryl substituted with 0-3 R 15 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 15 ;
R 6 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 16 , C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 16 , heteroaryl substituted with 0-3 R 16 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 16 ;
R 7 is, independently at each occurrence, H, alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
R 7 and one of said R 2 and R 3 , together with the nitrogen and carbon through which they are attached, may optionally form a heterocyclic or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally substituted with R 13 and any additional N atom substituted with C 1 -C 4 alkyl;
R 11 and R 12 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 13 , R 14 , R 15 , and R 16 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
wherein 1-3 carbon atoms in ring A may optionally be replaced with N;
said process comprising:
reacting G a1 -R 1 with a compound of formula IIA:
to form a compound of formula IIB:
wherein,
G a1 and G a2 are independently, activating groups;
G p1 is a protecting group;
T is —N(R 2 )(G p1 ), G a2 , or —N(R 2 )(R 3 );
wherein,
if T is —N(R 2 )(R 3 ), the compound of formula II is formed; or
if T is —N(R 2 )(G p1 ), the process further comprises:
deprotecting the compound of formula IIB to form a deprotected compound;
wherein,
if R 3 in the compound of formula II is H, then the compound of formula II is formed; or
if R 3 is other than H, the process further comprises reacting the deprotected compound with activated-R 3 ,
wherein the compound of formula II is formed; or
if T is G a2 , the process further comprises:
reacting the compound of formula IIB with —N(R 2 )(R 3 ) to form the compound of formula II; or
reacting the compound of formula IIB with —N(R 2 )(G p1 ) to form a protected compound;
deprotecting the protected compound to form a deprotected compound;
wherein,
if R 3 in the compound of formula II is H, then the compound of formula II is formed; or
if R 3 is other than H, the process further comprises reacting the deprotected compound with activated-R 3 ,
wherein the compound of formula II is formed.
40. The process of claim 39 , wherein activated-R 3 is halo-R 3 .
41. The process of claim 39 , wherein the compound of formula IIA is formed by:
reacting sulfamide with a compound of formula IIC:
thereby forming a compound of formula IIA.
42. The process of claim 41 , wherein the step of reacting sulfamide with a compound of formula IC is performed in the presence of a reducing agent.
43. The process of claim 41 , wherein the compound of formula IIC is formed by:
reacting a compound of formula IID:
with a compound of formula IIE:
wherein,
G a3 is an activating group;
thereby forming the compound of formula IIC.
44. The process of claim 43 , wherein the activating group is selected from the group consisting of halo, tosylate, mesylate, and triflate.
45. The process of claim 44 , wherein the activating group is Cl.
46. The process of claim 39 , wherein the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C 1 -C 6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
47. The process of claim 46 , wherein the protecting group is BOC.
48. The process of claim 39 , wherein the deprotecting step is performed in the presence of at least one agent selected from hydrochloric acid (HCl), tin(II)chloride, ammonium chloride, zinc, trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or aluminum chloride.
49. The process of claim 39 , wherein any one of the steps is performed at or above 30° C. or any one of the steps includes a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
50. The process of claim 39 , wherein any one of the steps is performed in: a protic solvent, an aprotic solvent, a polar solvent, a nonpolar solvent, a protic polar solvent, an aprotic nonpolar solvent, or an aprotic polar solvent.
51. A process for the preparation of a compound of formula II:
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof;
wherein:
n is an integer from 1 to 3
m is an integer from 0 to 4;
R 1 is C 6 -C 10 aryl substituted with 0-3 R 11 or heteroaryl substituted with 0-3 R 11 ;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol, or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ;
R 3 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkanol or C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 12 and said alkyl portions may be substituted with 0-3 R 13 ; or
R 2 and R 3 , together with the nitrogen through which they are attached, form a heterocyclic ring or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , where any carbon ring atom may be optionally substituted with R 12 , and where said additional N atom may be optionally substituted with C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl substituted with 0-3 R 14 , heteroaryl substituted with 0-3 R 14 , alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 5 is H;
R 6 is H, C 1 -C 6 alkyl, C 6 -C 10 aryl substituted with 0-3 R 16 , C 6 -C 10 aryl-C 1 -C 6 alkyl, where said aryl portion is substituted with 0-3 R 16 , heteroaryl substituted with 0-3 R 16 , or heteroaryl-C 1 -C 6 alkyl where said heteroaryl portion is substituted with 0-3 R 16 ;
R 7 is, independently at each occurrence, H, alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or
R 7 and one of said R 2 and R 3 , together with the nitrogen and carbon through which they are attached, may optionally form a heterocyclic or heterobicyclic ring of 3 to 12 ring atoms, where one carbon may be optionally substituted with R 13 and any additional N atom substituted with C 1 -C 4 alkyl;
R 11 and R 12 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, C 6 -C 10 arylsulfonamide, alkylamido, or arylamido;
R 13 , R 14 , R 15 , and R 16 are, independently at each occurrence, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
wherein 1-3 carbon atoms in ring A may optionally be replaced with N;
said process comprising:
reacting a compound of formula IIF:
with a compound of formula IIG:
to form a compound of formula IIB:
wherein,
T is —N(R 2 )(G p1 ), G a2 , or —N(R 2 )(R 3 );
wherein,
if T is —N(R 2 )(R 3 ), the compound of formula II is formed;
if T is —N(R 2 )(G p1 ), the process further comprises:
deprotecting the compound of formula IIB to form a deprotected compound;
wherein,
if R 3 in the compound of formula II is H, then the compound of formula II is formed; or
if R 3 is other than H, the process further comprises reacting the deprotected compound with activated-R 3 ,
wherein the compound of formula II is formed; or
if T is G a2 , the process further comprises:
reacting the compound of formula IIB with —N(R 2 )(R 3 ) to form the compound of formula II; or
reacting the compound of formula IIB with —N(R 2 )(G p1 ) to form a protected compound;
deprotecting the protected compound to form a deprotected compound;
wherein,
if R 3 in the compound of formula II is H, then the compound of formula II is formed; or
if R 3 is other than H, the process further comprises reacting the deprotected compound with activated-R 3 ,
wherein the compound of formula II is formed.
52. The process of claim 51 , wherein the reacting step is performed in the presence of dialkyl azodicarboxylate and triphenylphosphine (PPh 3 ).
53. The process of claim 52 , wherein the dialkyl azodicarboxylate is diisopropyl azodicarboxylate.
54. The process of claim 51 , wherein activated-R 3 is halo-R 3 .
55. The process of claim 51 , wherein T is Cl.
56. The process of claim 51 , wherein the compound of formula IIF is prepared by:
reacting sulfamide with a compound of formula IIH:
57. The process of claim 56 , wherein the compound of formula IIH is prepared by:
reducing a compound of formula IIJ:
58. The process of claim 57 , wherein the reducing step comprises contacting the compound of formula IIJ with borane.
59. The process of claim 57 , wherein the compound of formula IIJ is prepared by:
reacting R 1 NH 2 with a compound of formula IIK:
60. The process of claim 59 , wherein the reacting step is performed in the presence of a base.
61. The process of claim 60 , wherein the base is potassium tertiary butoxide (KOt-Bu).
62. The process of claim 51 , wherein the activating group is selected from the group consisting of halo, tosylate, mesylate, triflate, and oxo.
63. The process of claim 62 , wherein the activating group is Br.
64. The process of claim 51 , wherein the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, C 1 -C 6 alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
65. The process of claim 64 , wherein the protecting group is BOC.
66. The process of claim 51 , wherein the deprotecting step is performed in the presence of at least one agent selected from hydrochloric acid (HCl), tin(II)chloride, ammonium chloride, zinc, trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or aluminum chloride.
67. The process of claim 51 , wherein any one of steps is performed at or above 30° C. or any one of steps further comprises a purification step comprising at least one of: filtration, extraction, chromatography, trituration, or recrystallization.
68. The process of claim 51 , wherein any one of the steps is performed in: a protic solvent, an aprotic solvent, a polar solvent, a nonpolar solvent, a protic polar solvent, an aprotic nonpolar solvent, or an aprotic polar solvent.Cited by (0)
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